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Effect of efavirenz treatment on the pharmacokinetics of nelfinavir boosted by ritonavir in healthy volunteers
Author(s) -
La Porte C. J. L.,
De GraaffTeulen M. J. A.,
Colbers E. P. H.,
Voncken D. S.,
Ibanez S. Marco,
Koopmans P. P.,
Hekster Y. A.,
Burger D. M.
Publication year - 2004
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2004.02214.x
Subject(s) - nelfinavir , efavirenz , pharmacokinetics , ritonavir , tolerability , pharmacology , bioavailability , regimen , medicine , bioequivalence , chemistry , viral load , adverse effect , human immunodeficiency virus (hiv) , virology , antiretroviral therapy
Aims A once‐daily (q.d.) nucleoside‐sparing regimen can prevent mitochondrial toxicity, overcome viral resistance and improve compliance. In the present study the effect of efavirenz on the pharmacokinetics and tolerability of once‐daily nelfinavir/ritonavir was evaluated in healthy subjects. Methods This was a multiple‐dose, open‐label, single‐group, two‐period study in 24 healthy subjects. Each received from days 1–10 (period 1): 1875 mg nelfinavir plus 200 mg ritonavir q.d. with a 300‐kcal snack. During days 11–20 (period 2) efavirenz 600 mg q.d. was added to the regimen. Blood samples were collected up to 24 h after dosing on days 10 (period 1) and 20 (period 2). High‐performance liquid chromatography methods were used for the determination of the concentrations of all compounds. The main pharmacokinetic parameters were calculated using noncompartmental methods. Results All subjects completed the study. After the first period mean nelfinavir AUC 0−24 h , C max and C 24 were 49.6 mg h −1 l −1 , 5.0 mg l −1 and 0.37 mg l −1 , and the sum of nelfinavir plus its active metabolite M8 C 24 was 0.83 mg l −1 . The relative bioavailability, expressed as a geometric mean ratio (90% confidence interval) for nelfinavir AUC 0−24 h , C max and C 24 of period 2 compared with period 1 was: 1.30 (1.21, 1.40), 1.29 (1.19, 1.40) and 1.48 (1.32, 1.66). The sum of nelfinavir and M8 C 24 in period 2 was 0.99 mg l −1 , an increase of 19%. No serious adverse events occurred. Conclusions The studied regimens were well tolerated. Nelfinavir/ritonavir given together with efavirenz resulted in a 48% higher mean C 24 concentration for nelfinavir, and the sum of nelfinavir and M8 C 24 concentrations was 0.99 mg l −1 . Efavirenz exposure in this study was similar to that reported previously, and therefore can be used effectively in combination with ritonavir and nelfinavir.